Phenotypic Mutation 'Patently' (pdf version)
Allele | Patently |
Mutation Type |
missense
|
Chromosome | 8 |
Coordinate | 3,209,475 bp (GRCm39) |
Base Change | A ⇒ G (forward strand) |
Gene |
Insr
|
Gene Name | insulin receptor |
Synonym(s) | 4932439J01Rik, D630014A15Rik, IR, IR-B, IR-A, CD220 |
Chromosomal Location |
3,200,922-3,329,649 bp (-) (GRCm39)
|
MGI Phenotype |
FUNCTION: This gene encodes a member of the receptor tyrosine kinase family of transmembrane signaling proteins that play important roles in cell differentiation, growth and metabolism. The encoded preproprotein undergoes proteolytic processing to generate alpha and beta chains that form a disulfide-linked heterodimer which, in turn homodimerizes to form a mature, functional receptor. Mice lacking the encoded protein develop severe hyperglycemia and hyperketonemia, and die within a couple of days after birth as a result of diabetic ketoacidosis. [provided by RefSeq, Aug 2016] PHENOTYPE: Null mutants grow slowly and die by 7 days of age with ketoacidosis, high serum insulin and triglycerides, low glycogen stores and fatty livers. Tissue specific knockouts show milder lipid metabolism anomalies. Point mutation heterozygotes exhibit hyperglycemia, hyperinsulinemia and glucosuria. [provided by MGI curators]
|
Accession Number | NCBI RefSeq: NM_010568, NM_001330056; MGI:96575
|
Mapped | Yes |
Amino Acid Change |
Phenylalanine changed to Leucine
|
Institutional Source | Beutler Lab |
Gene Model |
predicted gene model for protein(s):
[ENSMUSP00000088837]
|
AlphaFold |
P15208 |
PDB Structure |
1.35A crystal structure of H-2Kb complexed with the GNYSFYAL peptide [X-RAY DIFFRACTION]
|
SMART Domains |
Protein: ENSMUSP00000088837 Gene: ENSMUSG00000005534 AA Change: F1203L
Domain | Start | End | E-Value | Type |
signal peptide
|
1 |
27 |
N/A |
INTRINSIC |
Pfam:Recep_L_domain
|
52 |
164 |
5e-28 |
PFAM |
FU
|
231 |
274 |
1.66e-10 |
SMART |
Pfam:Recep_L_domain
|
359 |
473 |
2.5e-30 |
PFAM |
FN3
|
496 |
602 |
4.02e1 |
SMART |
FN3
|
624 |
821 |
1.16e-6 |
SMART |
FN3
|
841 |
924 |
3.17e-4 |
SMART |
transmembrane domain
|
947 |
969 |
N/A |
INTRINSIC |
TyrKc
|
1013 |
1280 |
3.11e-134 |
SMART |
low complexity region
|
1303 |
1315 |
N/A |
INTRINSIC |
low complexity region
|
1327 |
1336 |
N/A |
INTRINSIC |
|
Predicted Effect |
probably damaging
PolyPhen 2
Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
(Using ENSMUST00000091291)
|
Predicted Effect |
unknown
|
Meta Mutation Damage Score |
0.9285 |
Is this an essential gene? |
Probably essential (E-score: 0.880) |
Phenotypic Category |
Autosomal Dominant |
Candidate Explorer Status |
loading ... |
Single pedigree Linkage Analysis Data
|
|
Penetrance | |
Alleles Listed at MGI | All Mutations and Alleles(19) : Chemically induced (ENU)(3) Gene trapped(2) Targeted(8) Transgenic(6)
|
Lab Alleles |
Allele | Source | Chr | Coord | Type | Predicted Effect | PPH Score |
IGL01099:Insr
|
APN |
8 |
3308682 |
missense |
probably damaging |
1.00 |
IGL01986:Insr
|
APN |
8 |
3208817 |
missense |
probably damaging |
1.00 |
IGL02135:Insr
|
APN |
8 |
3308741 |
missense |
probably damaging |
1.00 |
IGL02203:Insr
|
APN |
8 |
3205817 |
missense |
probably benign |
0.18 |
IGL02220:Insr
|
APN |
8 |
3209578 |
missense |
probably damaging |
1.00 |
IGL02678:Insr
|
APN |
8 |
3223570 |
missense |
probably benign |
0.00 |
IGL02961:Insr
|
APN |
8 |
3308785 |
missense |
probably benign |
0.08 |
IGL03099:Insr
|
APN |
8 |
3308715 |
missense |
probably damaging |
1.00 |
IGL03125:Insr
|
APN |
8 |
3234972 |
missense |
possibly damaging |
0.87 |
IGL03290:Insr
|
APN |
8 |
3308574 |
missense |
probably damaging |
1.00 |
gummi_bear
|
UTSW |
8 |
3211770 |
missense |
probably damaging |
1.00 |
jellybelly
|
UTSW |
8 |
3308841 |
missense |
probably damaging |
1.00 |
trolli
|
UTSW |
8 |
3248111 |
missense |
probably benign |
0.31 |
R0047:Insr
|
UTSW |
8 |
3252947 |
missense |
probably damaging |
0.97 |
R0053:Insr
|
UTSW |
8 |
3205683 |
missense |
probably damaging |
1.00 |
R0053:Insr
|
UTSW |
8 |
3205683 |
missense |
probably damaging |
1.00 |
R0480:Insr
|
UTSW |
8 |
3211770 |
missense |
probably damaging |
1.00 |
R0748:Insr
|
UTSW |
8 |
3308841 |
missense |
probably damaging |
1.00 |
R0919:Insr
|
UTSW |
8 |
3208769 |
missense |
probably damaging |
1.00 |
R1348:Insr
|
UTSW |
8 |
3242635 |
missense |
probably damaging |
1.00 |
R1467:Insr
|
UTSW |
8 |
3219720 |
missense |
probably damaging |
0.99 |
R1467:Insr
|
UTSW |
8 |
3219720 |
missense |
probably damaging |
0.99 |
R1568:Insr
|
UTSW |
8 |
3215576 |
missense |
probably benign |
|
R1768:Insr
|
UTSW |
8 |
3209561 |
missense |
probably damaging |
1.00 |
R2093:Insr
|
UTSW |
8 |
3254762 |
missense |
probably damaging |
1.00 |
R2111:Insr
|
UTSW |
8 |
3219748 |
missense |
probably benign |
0.17 |
R2112:Insr
|
UTSW |
8 |
3219748 |
missense |
probably benign |
0.17 |
R2352:Insr
|
UTSW |
8 |
3242593 |
missense |
probably damaging |
1.00 |
R2364:Insr
|
UTSW |
8 |
3224820 |
missense |
probably benign |
|
R2842:Insr
|
UTSW |
8 |
3252986 |
missense |
probably damaging |
1.00 |
R3162:Insr
|
UTSW |
8 |
3211416 |
missense |
possibly damaging |
0.65 |
R3162:Insr
|
UTSW |
8 |
3211416 |
missense |
possibly damaging |
0.65 |
R4081:Insr
|
UTSW |
8 |
3261391 |
missense |
probably benign |
0.00 |
R4441:Insr
|
UTSW |
8 |
3244902 |
missense |
probably benign |
0.00 |
R4672:Insr
|
UTSW |
8 |
3217501 |
critical splice donor site |
probably null |
|
R4687:Insr
|
UTSW |
8 |
3211709 |
missense |
probably benign |
0.42 |
R4708:Insr
|
UTSW |
8 |
3261346 |
intron |
probably benign |
|
R4890:Insr
|
UTSW |
8 |
3248234 |
missense |
probably benign |
0.16 |
R4949:Insr
|
UTSW |
8 |
3235059 |
missense |
probably benign |
0.04 |
R4996:Insr
|
UTSW |
8 |
3242665 |
missense |
probably null |
0.98 |
R5073:Insr
|
UTSW |
8 |
3209475 |
missense |
probably damaging |
1.00 |
R5176:Insr
|
UTSW |
8 |
3208742 |
missense |
probably benign |
0.03 |
R5200:Insr
|
UTSW |
8 |
3248059 |
critical splice donor site |
probably null |
|
R5323:Insr
|
UTSW |
8 |
3252902 |
missense |
probably benign |
0.02 |
R5453:Insr
|
UTSW |
8 |
3205694 |
missense |
probably benign |
0.06 |
R5516:Insr
|
UTSW |
8 |
3205764 |
nonsense |
probably null |
|
R5704:Insr
|
UTSW |
8 |
3235122 |
missense |
possibly damaging |
0.52 |
R5820:Insr
|
UTSW |
8 |
3205976 |
missense |
probably damaging |
1.00 |
R5879:Insr
|
UTSW |
8 |
3248173 |
nonsense |
probably null |
|
R5894:Insr
|
UTSW |
8 |
3224869 |
missense |
possibly damaging |
0.88 |
R5937:Insr
|
UTSW |
8 |
3224808 |
missense |
probably benign |
|
R5966:Insr
|
UTSW |
8 |
3308697 |
missense |
probably benign |
0.04 |
R6134:Insr
|
UTSW |
8 |
3242572 |
missense |
probably damaging |
1.00 |
R6352:Insr
|
UTSW |
8 |
3223479 |
critical splice donor site |
probably null |
|
R6423:Insr
|
UTSW |
8 |
3223566 |
missense |
probably benign |
|
R6687:Insr
|
UTSW |
8 |
3248111 |
missense |
probably benign |
0.31 |
R6985:Insr
|
UTSW |
8 |
3211372 |
missense |
possibly damaging |
0.87 |
R6993:Insr
|
UTSW |
8 |
3308752 |
missense |
probably damaging |
1.00 |
R7041:Insr
|
UTSW |
8 |
3308418 |
missense |
probably benign |
|
R7109:Insr
|
UTSW |
8 |
3308481 |
missense |
probably benign |
0.33 |
R7216:Insr
|
UTSW |
8 |
3253034 |
missense |
possibly damaging |
0.53 |
R7287:Insr
|
UTSW |
8 |
3219717 |
missense |
probably benign |
0.00 |
R7378:Insr
|
UTSW |
8 |
3248231 |
missense |
probably damaging |
1.00 |
R7525:Insr
|
UTSW |
8 |
3242642 |
missense |
probably damaging |
1.00 |
R7572:Insr
|
UTSW |
8 |
3223602 |
missense |
probably benign |
0.11 |
R7636:Insr
|
UTSW |
8 |
3308709 |
missense |
probably damaging |
1.00 |
R7684:Insr
|
UTSW |
8 |
3219753 |
missense |
possibly damaging |
0.85 |
R7840:Insr
|
UTSW |
8 |
3308415 |
missense |
probably benign |
0.04 |
R8075:Insr
|
UTSW |
8 |
3205862 |
missense |
probably benign |
0.17 |
R8161:Insr
|
UTSW |
8 |
3308660 |
missense |
probably damaging |
1.00 |
R8220:Insr
|
UTSW |
8 |
3208702 |
missense |
probably benign |
0.01 |
R8434:Insr
|
UTSW |
8 |
3215514 |
splice site |
probably benign |
|
R8810:Insr
|
UTSW |
8 |
3219714 |
missense |
probably benign |
|
R8865:Insr
|
UTSW |
8 |
3211358 |
missense |
probably damaging |
1.00 |
R8884:Insr
|
UTSW |
8 |
3205679 |
missense |
probably benign |
|
R9134:Insr
|
UTSW |
8 |
3308413 |
missense |
probably damaging |
1.00 |
R9359:Insr
|
UTSW |
8 |
3208717 |
missense |
probably damaging |
1.00 |
R9407:Insr
|
UTSW |
8 |
3235106 |
missense |
probably benign |
|
R9647:Insr
|
UTSW |
8 |
3205874 |
missense |
probably benign |
0.06 |
|
Mode of Inheritance |
Autosomal Dominant |
Local Stock | |
Repository | |
Last Updated |
2019-09-04 9:39 PM
by Diantha La Vine
|
Record Created |
2017-08-28 11:16 AM
by Bruce Beutler
|
Record Posted |
2018-10-25 |
Phenotypic Description |
The Patently phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R5073, some of which showed high insulin levels after a 30-minute glucose challenge (Figure 1).
|
Nature of Mutation |
Whole exome HiSeq sequencing of the G1 grandsire identified 113 mutations. The hyperinsulinemia phenotype was linked by continuous variable mapping to a mutation in Insr: a T to C transition at base pair 3,159,475 (v38) on chromosome 8, or base pair 120,175 in the GenBank genomic region NC_000074 encoding Insr. Linkage was found with a dominant model of inheritance, wherein 14 heterozygous mice departed phenotypically from 7 homozygous reference mice with a P value of 8.963 x 10-11 (Figure 2); no homozygous variant mice were born to pedigree R5073. The mutation corresponds to residue 4,096 in the mRNA sequence NM_010568 within exon 19 of 21 total exons.
4081 CTGAAGGATGGAGTCTTTACTGCTTCTTCTGAT
1198 -L--K--D--G--V--F--T--A--S--S--D-
|
The mutated nucleotide is indicated in red. The mutation results in a phenylalanine to leucine substitution at position 1,203 (F1203L) in the INSR protein, and is strongly predicted by PolyPhen-2 to be damaging (score = 1.000).
|
Illustration of Mutations in
Gene & Protein |
|
---|
Protein Prediction |
Insr encodes the ubiquitously expressed insulin receptor (IR), a member of the receptor tyrosine kinase family. The IR is either a dimer comprised of an extracellular α subunit and a membrane-spanning β subunit (αβ), or a heterotetramer of two α and two β subunits (α2β2); the α and β subunits are both coded by Insr. The α and β subunits are joined by disulfide bonds, which are proteolytically processed at a precursor processing enzyme cleavage site to generate the individual subunits (1;2). IR has a 27-amino acid signal sequence (Figure 3). The α subunit has two leucine-rich domains, a cysteine-rich domain, a fibronectin type III (FnIII) domain, a partial FnIII domain, and a long carboxy-terminal segment that has the furin cleavage site (3;4). The β subunit begins (after a short amino-terminal segment) with the completion of the partial FnIII domain of the α subunit, a third FnIII domain, a transmembrane domain, a juxtamembrane region, a tyrosine kinase domain, and a carboxy-terminal region. The Patently mutation results in a phenylalanine to leucine substitution at position 1,203 (F1203L), which is within the kinase domain of the β subunit. Please see the record gummi_bear for more information about Insr.
|
Putative Mechanism | The insulin signaling pathway regulates glucose uptake and release as well as the synthesis and storage of carbohydrates and lipids. Binding of insulin to the IR activates IR intrinsic tyrosine kinase activity, which propagates signaling to activate three main pathways: the MAP kinase, Cbl/CAP, and PI3K pathways (5). Phosphorylation of the juxtamembrane region of the IR recruits downstream signaling proteins (e.g., insulin receptor substrate proteins [Irs1 (see the record for runt) and Irs2 (see the record for dum_dum)] and Shc [see the record for shrine (Sch2)]). Mutations in INSR are associated with insulin-resistant diabetes mellitus with acanthosis nigricans [OMIM: #610549; (6-8)]. Acanthosis nigricans is a skin condition characterized by areas of discoloration in body folds and creases often in the armpits, groin, and neck. INSR mutations are also linked to familial hyperinsulinemic hypoglycemia 5 [HHF5; OMIM: #609968; (9)], leprechaunism [alternatively, Donohue syndrome; OMIM: #246200; (10-14)], and Rabson-Mendenhall syndrome [OMIM: #262190; (15;16)]. Patients with leprechaunism have growth delays, skin abnormalities, reduced muscle mass, phallic enlargement, and insulin resistance. Patients with Rabson-Mendenhall syndrome exhibit dental and skin abnormalities, abdominal distention, and phallic enlargement. Insr-deficient (Insr-/-) mice exhibited postnatal lethality within 72 hours after birth due to hyperglycemia, diabetic ketoacidosis, and hepatic steatosis (17;18). Insr-/- mice exhibit reduced body weights compared to wild-type controls. Rescue of IR expression in brain, liver, and pancreatic beta cells rescued the Insr-/- mice from neonatal death, prevented diabetes in most mice, and normalized adipose tissue content, lifespan, and reproductive function (19). Heterozygous Insr mice (Insr+/-) mice exhibited increased circulating insulin levels and insulin resistance (20;21). Heterozygous mice for an ENU-induced Insr alleles exhibited hyperglycemia and increased circulating insulin levels (MGI). The phenotype observed in the patently mice indicates loss of IR-associated function.
|
Primers |
PCR Primer
Patently_pcr_F: TAGCCATCTAAGAGAACCCAGA
Patently_pcr_R: TCAAGAATCCTTTCCCTCTGAG
Sequencing Primer
Patently_seq_F: CCCAGACAGATAAACCTTCATTTC
Patently_seq_R: CTCAGCTCTAGTGGTGCTTCAAG
|
Genotyping | PCR program 1) 94°C 2:00 2) 94°C 0:30 3) 55°C 0:30 4) 72°C 1:00 5) repeat steps (2-4) 40x 6) 72°C 10:00 7) 4°C hold
The following sequence of 400 nucleotides is amplified (chromosome 8, - strand):
1 tcaagaatcc tttccctctg agtttgcctg ctaccctcag ctctagtggt gcttcaaggg 61 gtagagcact caagatggta ggaggatgac ctgaaaaacc tgtgcactgt ttgttgtcag 121 actttggaat gacaagggac atctacgaga cagattacta tcggaaaggg ggcaagggac 181 tgcttcctgt gaggtggatg tcacctgagt ccctgaagga tggagtcttt actgcttctt 241 ctgatatgtg gtgagttata catacatggg tggatattag tgctgggctt gaactcctga 301 aggtgtccca ctaatgtgct catcaggagg tgatagagga aagcccatct ttcacatata 361 gaaatgaagg tttatctgtc tgggttctct tagatggcta
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red. |
References | 1. Ullrich, A., Bell, J. R., Chen, E. Y., Herrera, R., Petruzzelli, L. M., Dull, T. J., Gray, A., Coussens, L., Liao, Y. C., and Tsubokawa, M. (1985) Human Insulin Receptor and its Relationship to the Tyrosine Kinase Family of Oncogenes. Nature. 313, 756-761.
2. Sparrow, L. G., McKern, N. M., Gorman, J. J., Strike, P. M., Robinson, C. P., Bentley, J. D., and Ward, C. W. (1997) The Disulfide Bonds in the C-Terminal Domains of the Human Insulin Receptor Ectodomain. J Biol Chem. 272, 29460-29467.
3. Menting, J. G., Whittaker, J., Margetts, M. B., Whittaker, L. J., Kong, G. K., Smith, B. J., Watson, C. J., Zakova, L., Kletvikova, E., Jiracek, J., Chan, S. J., Steiner, D. F., Dodson, G. G., Brzozowski, A. M., Weiss, M. A., Ward, C. W., and Lawrence, M. C. (2013) How Insulin Engages its Primary Binding Site on the Insulin Receptor. Nature. 493, 241-245.
4. Croll, T. I., Smith, B. J., Margetts, M. B., Whittaker, J., Weiss, M. A., Ward, C. W., and Lawrence, M. C. (2016) Higher-Resolution Structure of the Human Insulin Receptor Ectodomain: Multi-Modal Inclusion of the Insert Domain. Structure. 24, 469-476.
6. Odawara, M., Kadowaki, T., Yamamoto, R., Shibasaki, Y., Tobe, K., Accili, D., Bevins, C., Mikami, Y., Matsuura, N., and Akanuma, Y. (1989) Human Diabetes Associated with a Mutation in the Tyrosine Kinase Domain of the Insulin Receptor. Science. 245, 66-68.
7. Moller, D. E., Cohen, O., Yamaguchi, Y., Assiz, R., Grigorescu, F., Eberle, A., Morrow, L. A., Moses, A. C., and Flier, J. S. (1994) Prevalence of Mutations in the Insulin Receptor Gene in Subjects with Features of the Type A Syndrome of Insulin Resistance. Diabetes. 43, 247-255.
8. Accili, D., Frapier, C., Mosthaf, L., McKeon, C., Elbein, S. C., Permutt, M. A., Ramos, E., Lander, E., Ullrich, A., and Taylor, S. I. (1989) A Mutation in the Insulin Receptor Gene that Impairs Transport of the Receptor to the Plasma Membrane and Causes Insulin-Resistant Diabetes. EMBO J. 8, 2509-2517.
9. Hojlund, K., Hansen, T., Lajer, M., Henriksen, J. E., Levin, K., Lindholm, J., Pedersen, O., and Beck-Nielsen, H. (2004) A Novel Syndrome of Autosomal-Dominant Hyperinsulinemic Hypoglycemia Linked to a Mutation in the Human Insulin Receptor Gene. Diabetes. 53, 1592-1598.
10. Psiachou, H., Mitton, S., Alaghband-Zadeh, J., Hone, J., Taylor, S. I., and Sinclair, L. (1993) Leprechaunism and Homozygous Nonsense Mutation in the Insulin Receptor Gene. Lancet. 342, 924.
11. Hone, J., Accili, D., al-Gazali, L. I., Lestringant, G., Orban, T., and Taylor, S. I. (1994) Homozygosity for a New Mutation (Ile119-->Met) in the Insulin Receptor Gene in Five Sibs with Familial Insulin Resistance. J Med Genet. 31, 715-716.
12. van der Vorm, E. R., Kuipers, A., Kielkopf-Renner, S., Krans, H. M., Moller, W., and Maassen, J. A. (1994) A Mutation in the Insulin Receptor that Impairs Proreceptor Processing but Not Insulin Binding. J Biol Chem. 269, 14297-14302.
16. Takahashi, Y., Kadowaki, H., Ando, A., Quin, J. D., MacCuish, A. C., Yazaki, Y., Akanuma, Y., and Kadowaki, T. (1998) Two Aberrant Splicings Caused by Mutations in the Insulin Receptor Gene in Cultured Lymphocytes from a Patient with Rabson-Mendenhall's Syndrome. J Clin Invest. 101, 588-594.
17. Accili, D., Drago, J., Lee, E. J., Johnson, M. D., Cool, M. H., Salvatore, P., Asico, L. D., Jose, P. A., Taylor, S. I., and Westphal, H. (1996) Early Neonatal Death in Mice Homozygous for a Null Allele of the Insulin Receptor Gene. Nat Genet. 12, 106-109.
18. Joshi, R. L., Lamothe, B., Cordonnier, N., Mesbah, K., Monthioux, E., Jami, J., and Bucchini, D. (1996) Targeted Disruption of the Insulin Receptor Gene in the Mouse Results in Neonatal Lethality. EMBO J. 15, 1542-1547.
19. Okamoto, H., Nakae, J., Kitamura, T., Park, B. C., Dragatsis, I., and Accili, D. (2004) Transgenic Rescue of Insulin Receptor-Deficient Mice. J Clin Invest. 114, 214-223.
20. Tanabe, K., Liu, Z., Patel, S., Doble, B. W., Li, L., Cras-Meneur, C., Martinez, S. C., Welling, C. M., White, M. F., Bernal-Mizrachi, E., Woodgett, J. R., and Permutt, M. A. (2008) Genetic Deficiency of Glycogen Synthase Kinase-3beta Corrects Diabetes in Mouse Models of Insulin Resistance. PLoS Biol. 6, e37.
21. Goldsworthy, M., Hugill, A., Freeman, H., Horner, E., Shimomura, K., Bogani, D., Pieles, G., Mijat, V., Arkell, R., Bhattacharya, S., Ashcroft, F. M., and Cox, R. D. (2008) Role of the Transcription Factor sox4 in Insulin Secretion and Impaired Glucose Tolerance. Diabetes. 57, 2234-2244.
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Science Writers | Anne Murray |
Illustrators | Diantha La Vine |
Authors | Zhao Zhang and Bruce Beutler |